Cyclosporins are cyclic oligopeptides of microbiological origin, which are used especially as immunosuppressives.
Cyclosporins, especially cyclosporin A, are used in connection with organ transplantation to prevent the rejection of the transplanted organ.
It has also been known that cyclosporins have anti-inflammatory and antiparasitic actions.
Therefore, the use of cyclosporins is not limited to immunosuppressives, but it also includes various autoimmune diseases and inflammatory conditions, especially inflammatory conditions in which autoimmune processes are involved. They include arthritic diseases, e.g., rheumatoid arthritis and rheumatic diseases.
Cyclosporins can be used as antiparasitic agents for the treatment of protozoal infections, e.g., malaria.
However, severe side effects, especially nephrotoxic effects, must be accepted with the cyclosporin formulations currently used in practice.
Cyclosporins are substances of a highly hydrophobic nature. Due to their poor solubility in water, it is difficult to process cyclosporins with the usual pharmaceutical carriers to prepare preparations of sufficient bioavailability.
The cyclosporin-containing pharmaceutical preparations disclosed in the prior art are based on the use of an alcohol and/or oils or similar vehicles in conjunction with a surface-active agent.
U.S. Pat. No. 4,388,307 discloses the solution of cyclosporin in a mixture of transesterification products of various oils formed with polyethylene glycol (e.g., Labrafil M 1499 CS a product of Gattefosse, France), as well as ethanol and a vegetable oil. However, the products thus obtained are unsuitable for intravenous administration because they contain oil. They can be administered only subcutaneously or intramuscularly.
According to product information on the Sandimmun drinking solution sold by Sandoz Pharmeceutical (Chapter XII, Sandoz-Pharma, Basel, 1984), cyclosporin is dissolved in a solution of polyoxyethylated castor oil (e.g., Cremophor EL, available from BASF) and ethanol. The disadvantage of these preparations is the fact that they are poorly tolerated by the patients, because anaphylactic reactions frequently develop (KAHAN et al., Lancet, 1984, I:52; LEUNISSEN, K. M. et al., Lancet, 1985, I:636).
PCT Application WO 92/09299 discloses oral liquid pharmaceutical preparations which contain a cyclosporin in a mixture of a hydrophilic solvent and a surface-active agent. Polyoxyethylene-polyoxypropylene block polymers (polyoxamers) with molecular weights of 1,000 to 15,500 are used as surface-active agents. The disadvantage of this formulation is the precipitation of the active ingredient in contact with aqueous solutions. These formulations are unsuitable for parenteral administration because of the solubilizing ability of the polyoxamers.